Xiu-bao Chang, Ph.D., is interested in overcoming multidrug resistance in human cancer cells.
It has been estimated that in 2012 more than 1.6 million new cases of cancer will be diagnosed and more than 500,000 people will die from cancer in the U.S. As such, cancer remains a major health problem.
Although advanced technologies play very important roles in treating patients, the treatments — such as chemotherapy — often fail to eradicate the tumors.
In fact, many cancers initially respond well to chemotherapy, but very often the tumors become resistant to multiple structurally unrelated anti-cancer drugs during or shortly after the chemotherapy, presumably because the drugs are unable to eradicate the multidrug resistance of cancer stem cells.
Several major classes of multidrug resistance mechanisms have been identified in many cancer cells:
- The overexpression of ATP-binding cassette (ABC) drug transporters, such as ABCB1, ABCC1 and/or ABCG2, pumps the structurally unrelated anti-cancer drugs out of cells and confers these cells resistant to the anti-cancer drugs.
- The overexpression of anti-apoptotic factors, such as B-cell lymphoma 2 (Bcl-2), prevents effective programmed cell death.
- The overexpression of the genes involved in drug metabolism, such as glutathione-S-transferase, alters the effective drug concentration inside of the cell.
- The overexpression of the proteins involved in the cell cycle, growth factor receptors, hormone receptors and/or transcription factors also contributes to multidrug resistance.
Dr. Chang's research has been funded by the National Institutes of Health, the Cystic Fibrosis Foundation and Mayo Clinic.
- Determining the molecular mechanism of ATP-dependent anti-cancer drug transport by ABCC1 or ABCG2. Dr. Chang has published many papers in this field and is working to better understand the molecular mechanism of ATP-dependent anticancer drug transport by ABC transporters.
- Determining the molecular mechanisms of multidrug resistance in breast cancer stem cells. Recent studies have shown that ABC transporters, such as ABCB1 or ABCG2, are almost universally expressed in the undifferentiated cancer stem cells and that its expression is shut down in many differentiated cells.
The expression of ABCB1 and ABCG2 in breast cancer stem cells will definitely confer the stem cells resistant to multiple anti-cancer drugs. However, whether overexpression of ABC transporters in breast cancer stem cells is the only mechanism of multidrug resistance is not yet well illustrated.
Dr. Chang and his colleagues have isolated breast cancer stem cells from either breast cancer cell lines or fresh breast cancer specimens and will determine whether or not other mechanisms of multidrug resistance also exist in breast cancer stem cells.
- Determining the vulnerable genes in breast cancer stem cells. Small interfering RNA (siRNA) will be used to determine the vulnerable genes in breast cancer stem cells.
- Developing a breast cancer stem cell-specific delivery system. Dr. Chang and his team have isolated ABCG2-specific ligands and breast cancer stem cell-specific ligands. These ligands will be used to make ligand-coated nanoparticles — such as liposomes — harboring therapeutic agents, such as vulnerable gene siRNA, kinase inhibitors and/or anti-cancer drugs.
Upon treatment with breast cancer stem cell ligand-coated liposomes (harboring therapeutic agents), the multidrug-resistant breast cancer stem cells might be efficiently killed or hypersensitized to anti-cancer drugs.
Therefore, the combined treatments of a breast cancer stem cell-specific delivery system and conventional chemotherapy will not only get rid of the multidrug-resistant breast cancer stem cells, but also eradicate the differentiated breast cancer cells.
- Determining the molecular mechanism of immunomodulatory drug (IMiD) resistance in multiple myeloma and overcoming IMiD resistance in multiple myeloma cells. IMiDs, such as thalidomide, lenalidomide or pomalidomide, are profoundly active in the treatment of multiple myeloma and related diseases.
Despite the fact that treatment with IMiDs has dramatically improved survival for patients with multiple myeloma, the molecular mechanism of action of these IMiDs remains unclear. In addition, the majority of the patients treated with IMiDs develop resistance over time, and the molecular mechanisms of IMiD resistance remain unknown.
Understanding the molecular mechanism of IMiD resistance may open the door for Dr. Chang and his colleagues to design a novel therapeutic approach to treat multiple myeloma patients.
Significance to patient care
Dr. Chang's research into breast cancer stem cells and IMiD resistance in multiple myeloma patients will help him and his team design novel therapeutic approaches to treat patients with breast cancer and multiple myeloma.
- Associate Editor, Bioinfo Publications, 2011-present
- Associate Editor, International Journal of Molecular Biology, 2010-present
- Editorial Board Member — Frontiers in Cancer Genetics (2011-present) and the International Journal of Biochemistry and Molecular Biology (2009-present)
- Reviewer — Research Grants Council of Hong Kong, Israel Science Foundation, WELBIO (Belgium)